title: Randomized phase 2 study of pegylated SN-38 (EZN-2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer.
abstract: BACKGROUND
  Irinotecan is cytotoxic in patients with advanced colorectal cancer (CRC). SN-38 (10-hydroxy-7-ethyl-camptothecin) is the active metabolite of irinotecan. Attachment of polyethylene glycol (PEG) polymer chains (pegylation) to SN-38 (EZN-2208) increases the solubility, exposure, and half-life of SN-38. Preclinical studies demonstrated superior in vitro efficacy of EZN-2208 when it was tested in irinotecan-refractory human CRC cell lines.
  
  
  METHODS
  Patients with metastatic or locally recurrent CRC who had previously received 5-flurouracil (5-FU), oxaliplatin, and irinotecan were assigned to receive EZN-2208 monotherapy (9 mg/m(2) on days 1, 8, and 15 every 28 days for patients with KRAS-mutant tumors only [arm A]), and patients with KRAS wild-type tumors were randomized (2:1) to receive either EZN-2208 plus cetuximab (400 mg/m(2) loading dose on day 1 followed by 250 mg/m(2) weekly starting on day 8 [arm B]) or irinotecan 125 mg/m(2) on days 1 and 8 every 21 days plus cetuximab at the same doses indicated above (arm C).
  
  
  RESULTS
  The overall response rate and progression-free survival were 0% and 1.8 months, respectively, in arm A; 10.7% and 4.9 months (95% confidence interval [CI], 3.2-5.8 months), respectively, in arm B; and 14.3% and 3.7 months (95% CI, 2.1-5.8 months), respectively, in arm C. EZN-2208 was well tolerated in combination with cetuximab. No statistically significant difference in survival was observed between arm B (9.8 months; 95% CI, 7.2-11.2 months) and arm C (9.1 months; 95% CI, 6.0-13.0 months).
  
  
  CONCLUSIONS
  EZN-2208, either as monotherapy or in combination with cetuximab, was well tolerated in patients with refractory CRC. Overall survival and progression-free survival were similar in the cetuximab plus irinotecan arm and the EZN-2208 arm.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Garrett
authors.forename: Tanios S
authors.initials: TS
authors.lastname: Bekaii-Saab
authors.forename: Theresa
authors.initials: T
authors.lastname: Ryan
authors.forename: George A
authors.initials: GA
authors.lastname: Fisher
authors.forename: Sally
authors.initials: S
authors.lastname: Clive
authors.forename: Petr
authors.initials: P
authors.lastname: Kavan
authors.forename: Einat
authors.initials: E
authors.lastname: Shacham-Shmueli
authors.forename: Aby
authors.initials: A
authors.lastname: Buchbinder
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D011905:Genes, ras; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; C528970:EZN-2208; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011092:Polyethylene Glycols; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002166:Camptothecin
keywords: EZN-2208; SN-38; colorectal cancer; pegylated; randomized phase 2